Download GHB Withdrawal Syndrome

Patients with
a history of
around-theclock use of
gamma
hydroxybutyrate
may present
a disturbing
and difficult
to manage
clinical picture.
GHB
Withdrawal
Syndrome
March 2001
Karen Miotto, MD
UCLA Integrated
Substance Abuse Program
[email protected]
Brett Roth, MD, FACEP
UTSW Toxicology
Training Service
[email protected]
Texas Commission on
Alcohol and Drug Abuse
www.tcada.state.tx.us
© March 2001, Texas Commission on Alcohol and Drug Abuse (TCADA), Austin, Texas.
TCADA grants full permission to reproduce and distribute any part of this document for
non-commercial use. Appropriate credit is appreciated. TCADA is a state agency headed by six
commissioners appointed by the governor. TCADA provides funding for substance abuse
prevention, intervention and treatment programs and licenses chemical dependency counselors
and facilities in the state.
Texas Commission on
Alcohol and Drug Abuse
PO Box 80529 • Austin, Texas 78708-0529
9001 N. IH-35, Ste. 105 • Austin, Texas 78753-5233
(512) 349-6600 • (800) 832-9623
Web site: www.tcada.state.tx.us
Emerging trends in GHB
withdrawl syndrome, detoxification
About this article
This article details the
experience of two physicians
in different metropolitan
areas who have treated a
number of patients who
have gone through what
appears to be withdrawal
after the repeated use of
GHB. They describe a syndrome that has similarities
to both alcohol withdrawal
and benzodiazepine (or
other sedative hypnotic)
withdrawal.
Karen Miotto, MD
UCLA Integrated
Substance Abuse Program
[email protected]
Brett Roth, MD, FACEP
UTSW Toxicology
Training Service
[email protected]
Summary
➣ A GHB withdrawal syndrome that has aspects of alcohol
withdrawal (delirium tremens) and benzodiazepine withdrawal (long duration of symptoms) is described.
➣ The syndrome appears to manifest itself in those patients
who have self-administered GHB in an around-the-clock
dosing schedule, i.e. users who take GHB every 2-3 hours
are at increased risk for the emergence of severe symptoms.
GHB withdrawal can occur after several months of aroundthe-clock use.
It is not intended as a set
of specific recommendations
for management of the
described syndrome but
rather as an alert that they
have attended patients presenting with a specific and
unique symptom complex
related to the repeated
ingestion of GHB.
➣ Management of the withdrawal syndrome has necessitated
the use of high dosages of sedative-hypnotic and physical
restraints to control the confusion, delirium, psychosis,
and resultant agitation. In the past five years there has been
an increase in patients presenting in GHB withdrawal at
emergency rooms and behavioral health providers. Stricter
federal and state controls on the distribution of GHB have
led to the use of a number of GHB analogs including GBL,
which produce similar states of withdrawal.
They acknowledge the
management of the syndrome has been arduous and
invite others who have witnessed similar patients to
contact them to more clearly
define patient management
and the pathophysiologic
mechanisms underlying the
proposed disorder.
• Medical personnel who might come in contact with
patients using dietary supplements and/or drugs of abuse
should be aware of the possibility of GHB dependence
and withdrawal in some of their patients.
— John P. Keppler, MD,
Clinical Director,
TCADA
➣ Recommendations —
• Any patient who has been using this drug should be carefully questioned regarding the frequency of GHB use in
addition to the amount and duration.
• GHB withdrawal in its florid state needs to be treated in
a hospital setting.
Overview
Many patients who use GHB are not dependent
and can be educated about the risks of GHB
and referred for outpatient therapy. Experience
has shown that patients with a history of
around-the-clock dosing may present with a disturbing and difficult-to-manage clinical picture.
This hallmark of severe dependence, i.e., the
administration of GHB every two to four hours,
24 hours a day, begins with anxiety, insomnia,
tremor, and episodes of tachycardia that develop
with discontinuation. Symptoms may rapidly
progress to a state of uncontrolled delirium and
agitation. Once GHB dependence is recognized,
aggressive efforts are generally necessary to ameliorate the patient’s signs and symptoms of withdrawal. This is most effectively achieved by
detoxifying the patient in an in-patient medical or
psychiatric facility. In-patient therapy for GHB
withdrawal helps to insure patient safety and dignity and may also decrease the risk of relapse.
Settings where GHB withdrawal may be recognized include the emergency department after
treatment of an acute overdose; hospital wards
during therapy for unrelated conditions, such as
trauma or medical illnesses; physician offices;
psychiatric facilities; and detoxification centers.
Assessing GHB Withdrawal
Symptoms
Due to the drug’s short duration of action and
rapid elimination,1 the signs and symptoms of
GHB abstinence syndrome appear rapidly,
generally within 1-6 hours after the last dose.
Table 1 describes the symptoms commonly
encountered during GHB withdrawal and the
temporal pattern of their occurrence.2 Note that
the course of GHB withdrawal symptoms may
be prolonged, persisting for up to two weeks or
more. After acute detoxification, many patients
report persistent symptoms of anxiety, depression, insomnia, and cognitive deficits which
often continue for many months.3 Concurrent
alcohol and sedative-hypnotic use, the daily
dose of GHB consumed, and the existence
of concurrent psychiatric illness appear to be
4
important factors in determining the severity of
GHB withdrawal.3
Alcohol vs. GHB Withdrawal
It appears that GHB withdrawal shares features of
both alcohol withdrawal and benzodiazepine withdrawal (i.e., prolonged duration of symptoms).
Agitation can be ameliorated by pharmacological therapy but the delirium is highly resistant.
Unlike alcohol or sedative-hypnotic withdrawal,
the initial symptoms of GHB withdrawal appear
early, often within an hour, and delirium evolves
more rapidly.3 Peak manifestations of the withdrawal syndrome may occur within 24 hours,
and like delirium tremens, may last up to
14 days.2,3 Neuropsychiatric symptoms including
confusion, psychosis, and delirium are similar to
those seen with delirium tremens4 and appear to
be the prominent features of GHB withdrawal.
Unlike delirium tremens from alcohol, autonomic
instability (diaphoresis, tremor, hypertension,
and temperature disregulation) appears to be
slightly less severe. Brief episodes of significant
tachycardia begin (heart rate 160 or more) early
in GHB withdrawal.
Treatment Guidelines for
GHB Withdrawal
The following information is based on a review
of the limited medical literature and clinical
experience, and is not intended for the use of
GHB-dependent individuals without the supervision of a medical doctor. To date, there is no
medical literature establishing the safety and efficacy of any particular GHB detoxification protocol. Controlled trials are needed.
These treatment guidelines should be considered
as a starting point for the treatment of more
severe cases of GHB withdrawal syndrome. Less
tolerant individuals may require a less aggressive
approach.
GHB Withdrawal Syndrome
TABLE 1: TEMPORAL PATTERN OF THE SYMPTOMS OF GHB WITHDRAWAL2
(Symptoms do not always progress from mild to severe in a predictable fashion.)
SYMPTOMS:
Early
(1-24 hours)
Progressive
(1-6 days)
Episodic when
waning (7-14 days)
Anxiety/Restlessness
++
+++
++
Insomnia
+++
+++
++
Tremor
+
++
+
Confusion
++
+++
++
Delirium
++
+++
+++
Auditory, tactile, and visual hallucinations
+
+++
++
+++
+++
++
Hypertension
+
++
+
Nausea
++
+
+
Vomiting
++
+
0
Diaphoresis
+
++
+
Intermittent Tachycardia
Key: Mild = +, Moderate = ++, Severe = +++
Other signs and symptoms of acute GHB abstinence syndrome may include2-5
• Anorexia, abdominal cramps
• Nightmares
• Impaired concentration, memory, and judgment
• Increased sensitivity to sounds and tactile sensations
• Delusions
• Tonic-clonic activity (it is unclear if actual seizures occur during GHB withdrawal)
• Elevated temperature
• Dehydration
Recommendations for
In-patient Therapy
While successful attempts at self-tapering doses
of GHB have been reported among abusers,
most GHB-dependent individuals are unable to
tolerate the symptoms of withdrawal. Physicians
should be aware that patients disabled by lack
of sleep, and other disturbing symptoms, may
attempt to self-detoxify by taking large doses
of alcohol or medications, including benzodiazepines. Use of multiple substances in an
unsupervised setting may place the patient in
danger of drug overdose and can contribute to
withdrawal severity. For the above reasons, an
aggressive 7-14 day inpatient strategy with close
follow-up care is recommended.
GHB Withdrawal Syndrome
Benzodiazepines
Benzodiazepines such as lorazepam (Ativan),
chlordiazepoxide (Librium), and diazepam
(Valium), are useful in ameliorating some of
the signs and symptoms of GHB withdrawal.
Loading doses of oral or intravenous benzodiazepines do not decrease the likelihood of withdrawal delirium, but are important for controlling
psychotic agitation.3 Most patients in GHB withdrawal have an extremely high tolerance to the
sedating effects of benzodiazepines and require
large frequent doses similar to those required for
the treatment of severe alcohol withdrawal. In one
case treated in an intensive care unit, one author
(BR) described a patient who required 129 mg
of lorazepam and 40 mg of diazepam during the
first day of hospitalization.2 Other case reports
of severe withdrawal describe using 507 mg of
lorazepam and 120 mg of diazepam over 90 hours
to control agitation.6 Such large benzodiazepine
5
doses necessitate close medical attention and
the application of continuous pulse oximetry to
monitor for oxygen desaturation. A larger sample
of patients in GHB withdrawal is necessary before
general dosing for benzodiazepine administration
can be established.
Other Medications
Barbiturates: Barbiturates in combination with
benzodiazepines have been used successfully to
lower benzodiazepine requirements and improve
withdrawal symptoms. Pentobarbital, a short
acting parenteral barbiturate, can be titrated
intravenously in 100-200 mg increments to
symptoms. Phenobarbital also may be used
and has the advantage of providing a longer
duration of action due to its longer half life
(T1/2 ~90 hours). Depending on the dose of benzodiazepine already received, phenobarbital may
be titrated in 250 mg increments intravenously
to achieve a serum phenobarbital level of 5-15
micrograms per milliliter with most patients
requiring approximately 500 mg for immediate
control of symptoms. Tapering oral doses of
both benzodiazepines and barbiturates can then
be used over the course of several weeks when
the patient’s condition has stabilized.
Sedating Agents: Propofol is an anesthetic
agent used for sedation in the ICU that has
been reported to provide relief for the psychotic
agitation in patients in severe GHB withdrawal.
Other Anticonvulsants: Patients in GHB
withdrawal often demonstrate twitching,
grimacing, and tonic-clonic movements. The
concern of withdrawal seizure activity has not
been adequately evaluated by current studies
and even though some believe these movements
represent myoclonus, rather than true seizures,
the addition of anticonvulsants to the treatment
regimen of patients with twitching or tonic-clonic
activity seems wise.
Gabapentin has been used anecdotally (300 mg
three times a day on day one, increasing the dose
to 2-3 grams over the course of a week) with the
goal of decreasing excitotoxicity and agitation.
6
Sodium Divalproate increases endogenous GHB
levels and has been considered in the treatment
of GHB withdrawal. While Sodium Divalproate
can transiently elevate transaminase levels, elevated transaminase levels have been reported in
patients during GHB withdrawal that were not
treated with Sodium Divalproate. The significance of elevated liver function tests during
GHB withdrawal has not been determined.
Antihypertensive Medications: Patients may
request medications such as beta-blockers for the
treatment of minor autonomic hyperactivity such
as elevated heart rate, elevation of blood pressure,
sweating, tremor, or panic attacks. Although
blocking beta-adrenergic receptors is effective in
decreasing autonomic symptoms, it is not effective
in preventing delirium or psychosis, and thus
should not be prescribed. However, clonidine has
been used to provide relief of the intermittent
episodes of tachycardia, which are described by
patients as their heart “pounding” or “racing.”
Animal models of agitated delirium suggest
that beta-blockers used to control vital sign
abnormalities via peripheral beta-blockade,
without central nervous system sedation, may
be detrimental.7 In the setting of catecholamine
excess, beta-blockade may cause unopposed
alpha-1 receptor stimulation and paradoxical
vasospasm leading to worsening hypertension
and even coronary ischemia.8 For these reasons,
the use of beta-blockers in the setting of severe
withdrawal is not recommended.
Haloperidol and Other Antipsychotic
Medications: Clinicians have reported using
large doses of antipsychotic medication in an
attempt to control GHB withdrawal psychosis.9
In the authors’ experience, antipsychotic medication, such as haloperidol in large doses, provided
limited control of symptoms. Benzodiazepines
and phenobarbital have been shown to provide
better control of psychotic symptoms.9 Beware
of dystonic reactions and temperature disregulation if haloperidol or other neuroleptics are used
with agitated, hyperthermic patients. Neuroleptics
may also increase the risk of neuroleptic malignant syndrome and malignant hyperthermia.
GHB Withdrawal Syndrome
Vitamins: Concerns are raised that GHBdependent patients may have vitamin deficiencies due to poor nutritional habits. One case
of thiamine deficiency has been reported.10
High-potency multivitamins and thiamine may
be beneficial. The role of thiamine in delirium
tremens and associated neurological syndromes
is well known in cases of alcoholism and
remains to be determined in GHB.
Medical Complications of
GHB Withdrawal
Fluid and Electrolyte Imbalance: Clinical
management of GHB withdrawal requires maintaining the patient’s fluid and electrolyte balance
during detoxification. Many patients lose their
appetite and ignore food and water. Patients who
become dehydrated should receive intravenous
fluids, electrolytes, dextrose, and thiamine.
Fever: Elevation of temperature has been reported
in severe cases of GHB withdrawal.9 Patients often
become extremely agitated and require the application of four-point restraints for safety. Evaluation
of potential sources of infection, such as meningitis
or aspiration pneumonia, is essential. This is particularly true in patients who receive high doses of
medications to control withdrawal.
Rhabdomyolysis: Severe agitation may lead
to rhabdomyolysis requiring fluid therapy to
establish a brisk urine output and the need for
aggressive sedation to decrease muscular activity.
Death: One case of GHB withdrawal resulted
in an unexpected death on hospital day 12.2
Whether or not this patient’s death was directly
related to the GHB withdrawal syndrome is
speculative. Autopsy results failed to implicate
other medical causes for the patient’s death.
Further research is needed to determine if other
GHB fatalities have occurred during withdrawal.
GHB Withdrawal Syndrome
Hypothesis for the Mechanism of
GHB Tolerance and Withdrawal
Specific detoxification protocols for GHB
withdrawal await a better understanding of
the neurobiology of GHB addiction. Clinical
observations suggest that GHB abuse leads to
tolerance and increased frequency of dosing.
In Figure 1, it is postulated that GHB tolerance
is associated with dysregulation of inhibitory
neurotransmitter systems including GABA and
GHB. Decreased GHB consumption and the
withdrawal state may be associated with excitotoxicity involving neurotransmitter systems such
as glutamate, norepinephrine, and dopamine.
Pathophysiology
Pathophysiologic mechanisms of withdrawal are
complex and vary according to the substance
abused (see Table 2).
Perhaps the most important activity GHB possesses with regard to its withdrawal syndrome is
a close metabolic relationship with GABA. An
in vivo conversion of radioactive GHB into
GABA has been described and it appears that,
along with exerting a distinct effect at special
GHB receptors, GHB possesses “GABAminergic”
properties as well.11 Current research has proposed
that GHB modulates both GABA A receptors
and GABA B receptors.12 The end result, acutely,
is neuroinhibition with physiologic tolerance
developing with frequent dosing.
Clinical similarities between GHB withdrawal
and other sedative hypnotic withdrawal syndromes
suggest that shared common mechanisms of
central action may exist. Ethanol increases
endogenous levels of GHB and acts synergistically
with GHB to produce central nervous system
and respiratory depression.13 Cross-tolerance has
been demonstrated between ethanol and GHB
in rats, and GHB has been used to suppress
withdrawal symptoms in patients presenting in
7
FIGURE 1. CYCLE OF ABUSE, PHYSIOLOGIC TOLERANCE
AND GHB WITHDRAWAL PATHOPHYSIOLOGY
GHB ABUSE
TOLERANCE
Down regulation of inhibitory
GABA-A, GABA-B, GHB receptors
DECREASED GHB CONSUMPTION
DYSINHIBITION OF EXCITATORY NEUROTRANSMITTERS
(Glutamate, Norepinephrine, Dopamine)
WITHDRAWAL
Anxiety • Restlessness • Insomnia • Tremor • Confusion
Delirium • Hallucinations • Tachycardia • Hypertension
Nausea • Vomiting • Diaphoresis
acute alcohol withdrawal.14,15 Chronic alcohol,
benzodiazepine, and GHB administration
have been shown to cause down-regulation of
inhibitory GABA receptors.16,17 During benzodiazepine withdrawal, GABA synaptic activity
becomes so diminished that inhibitory control
of excitatory neurotransmitters and pathways is
also lost, and the subsequent withdrawal syndrome ensues.18 A similar type of situation may
be occurring with GHB withdrawal. One also
may speculate that an excess dopaminergic state,
shown to be associated with psychotic hallucinosis,19 may be part of the GHB withdrawal
syndrome. Baclofen, a GABA B receptor agonist
has also been associated with severe psychological reactions during withdrawal states.20,21
Undoubtedly, several mechanisms are responsible for the GHB withdrawal state and future
studies are necessary to clarify these mechanisms.
8
Contribute Your Clinical
Case Experiences
The authors welcome any feedback regarding the
success or failure of any treatment regimens being
used in your area. Your feedback will allow these
guidelines to be refined and more closely tailored
to the severity of withdrawal experienced by each
patient. Your communication of the successes
and failures of different treatment approaches
will help achieve the goal of improved care for
patients with GHB withdrawal.
The authors are particularly interested in knowing about successful pharmacologic therapies and
doses, tapering regimens, behavioral therapies, as
well as how, or if, successful detoxification has
been achieved without patient hospitalization.
GHB Withdrawal Syndrome
TABLE 2. COMPARISON BETWEEN VARIOUS WITHDRAWAL SYNDROMES2
Substance
Onset/
Duration
GHB
1-3 hrs/
6-12 days
Mild
Severe
?
Benzodiazepine
1-3 days/
5-9 days
Moderate
Moderate
1%
Usually >6 hrs/
10-14 days
Severe
Moderate
to Severe
5-15%
Ethanol
Autonomic Neuropsychiatric
Instability
Symptoms
Conclusion
Gamma-hydroxybutyrate (GHB) is an emerging
drug of abuse with anesthetic and sedativehypnotic effects. GHB is easily made and sold
under multiple names such as Renutrient and
Revitalize Plus. In addition, GHB analogs
such as Gamma-butyrolactone (GBL) continue
to surface, often disguised as health food
supplements, and can be readily found on the
Internet. These frequent name changes and
analog preparations have contributed to the lack
of awareness of the risks and dangers associated
with GHB use. This has also resulted in confusion for medical care providers who provide care
for patients in GHB withdrawal.
GHB Withdrawal Syndrome
Mortality
Possible Mechanism
inducing W/D State
Loss GHB, GABA A, and
GABA B mediated inhibition
Loss of GABA A
mediated inhibition
Loss of GABA A mediated
inhibition, disinhibition
of NMDA receptors
Emerging medical information has recently provided new insights about GHB dependence and
withdrawal. However, research on treatment is
an important area that remains to be developed.
This manuscript was created to alert medical
care providers to some of the risks and dangers
associated with GHB withdrawal. It is the
authors’ experience that many clinicians are
unaware of the signs of GHB withdrawal and
similarly do not know how to provide symptomatic relief for GHB withdrawal symptoms.
This has deterred patients from seeking the
proper medical care. This manuscript was created
to inform and provide health care providers
with a framework for treatment, and is not
intended that users of GHB use this information
as a guide to self-medicate.
9
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GHB Withdrawal Syndrome